New research pinpoints key pathways in prostate cancer's vulnerability to ferroptosis

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In a recent review published in the journal Nature Reviews Urology, researchers examined the molecular mechanisms and metabolic processes that drive ferroptosis — a form of cell death that plays a significant role in prostate cancer. They also connected pathways involved in ferroptosis to the metabolic reprogramming that occurs in prostate cancer cells to highlight potential avenues of targeted therapeutic interventions.

Perspective: Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Image Credit: MattL_Images / Shutterstock

Perspective: Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Image Credit: MattL_Images / Shutterstock

Background

Although the five-year survival rate in cases of localized prostate cancer is very promising (greater than 99%), metastasis or the prostate cancer progressing to the castration-resistant form of prostate cancer reduces the five-year survival rate to between 30% and 40%. Furthermore, while treatment options such as radiotherapy, chemotherapy, immunotherapy, and second-generation androgen receptor-signaling inhibitors can be used to treat advanced prostate cancer, these therapies only increase the survival rate by two to three years. Understanding the underlying mechanisms of prostate cancer can help improve and initiate early treatment.

Recent research has found that a pathway of regulated cell death, called ferroptosis, plays a significant role in the development of prostate cancer. Ferroptosis differs from the other forms of cell death, such as autophagy, apoptosis, and necrosis, in that it is iron-dependent and is driven by lipid peroxide build-up. Studies have found that the suppression of ferroptosis is linked to tumor pathogenesis, especially in prostate cancer.

Ferroptosis

Ferroptosis does not have the typical characteristics of apoptosis, such as the condensation of chromatin, apoptotic body formation, and cytoskeletal breakdown. Neither does it show the hallmarks of necrosis and autophagy, such as the swelling of organelles and the formation of the autophagosomes, respectively.

During ferroptosis, the mitochondrial size and cristae of the cells reduce, and the membrane density increases. Additionally, the polyunsaturated fatty acids that are part of the phospholipid membrane form peroxides. The lipid peroxidation could be initiated due to oxidation from iron overload, the mitochondria, or the production of reactive oxygen species due to iron. The lipid peroxidation process results in widespread damage and oxidative injury, leading to cell death.

Cells contain various intrinsic systems to circumvent lipid peroxidation and ferroptosis. The classical method involves the use of glutathione and glutathione peroxidase 4 to decrease the levels of lipid hydroperoxides, preserving the integrity of the phospholipid bilayer and preventing ferroptosis. Inhibition of ferroptosis can also occur through ferroptosis suppressor protein 1 or dihydroorotate dehydrogenase.

Ferroptosis and cancer

Given the association between ferroptosis and polyunsaturated fatty acids, cancer cells, which undergo substantial metabolic reprogramming and produce reactive oxygen species, are especially susceptible to ferroptosis. Cells in malignant tumors have higher energy and iron demands, which increases their susceptibility to ferroptosis. Prostate cancer cells depend on lipid metabolism for their high energy requirements, which causes the fatty acid metabolism in prostate cancer cells to be dysregulated.

Furthermore, factors such as lipid metabolism gene upregulation, rewiring of the oxidative phosphorylation metabolism, and increased tricarboxylic acid flux have been observed in both early and late-stage prostate cancer cells. These processes could increase the intracellular reactive oxygen species burden, promote lipid peroxidation, and cause perturbations in iron homeostasis.

The review discussed various mechanisms through which the susceptibility of cancer cells to ferroptosis could be exploited as potential treatment avenues for advanced cancers. Targeting the defense mechanisms that inhibit ferroptosis is a promising approach. Studies have suggested that targeting the glutathione peroxidase 4 inhibition mechanism could induce ferroptosis in cancer cells that do not respond to other treatment options.

Research also indicated that dihydroorotate dehydrogenase was not the primary ferroptosis inhibitor in cancer cells, and therefore, targeting dihydroorotate dehydrogenase might not be as effective as deletion of ferroptosis suppressor protein 1.

Furthermore, these studies highlighted the need to thoroughly understand the pitfalls and benefits of the various mechanisms to induce ferroptosis. Knockout studies in murine models revealed that glutathione peroxidase 4 was essential in various other processes and required for survival, while knocking out ferroptosis suppressor protein 1 resulted in no developmental changes, suggesting the latter to be a preferable method to induce ferroptosis.

This comprehensive review provided a detailed discussion of the various metabolic processes that could be exploited to make cancer cells vulnerable to ferroptosis. These methods included modulating the balance between mono- and polyunsaturated fatty acids, de-novo lipogenesis, de-novo synthesis of polyunsaturated fatty acids, and β oxidation. The researchers also expanded on the role of iron, cystine, glutamate, and glutathione metabolism in ferroptosis.

Conclusions

To summarize, the review provided an in-depth view of the regulated cell death process of ferroptosis, the factors that make cancer cells susceptible to ferroptosis, and its importance in prostate cancer therapy. They discussed the pathways through which ferroptosis is suppressed in cancer cells and the metabolic mechanisms that must be targeted to induce ferroptosis in prostate cancer cells selectively.

Journal reference:
  • Anh, H., Dominic, A., Lujan, F. E., Senthilkumar, S., Bhattacharya, P. K., Frigo, D. E., & Subramani, E. (2024). Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Nature Reviews Urology. DOI: 10.1038/s41585024008699, https://www.nature.com/articles/s41585-024-00869-9
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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